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Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori

Infection of the stomach by Helicobacter pylori is a major risk factor for the development of gastric cancer. Colonization of the gastric epithelium leads to the activation of multiple disease-related signaling pathways. Serine protease HtrA represents an important secreted virulence factor that med...

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Autores principales: Sharafutdinov, Irshad, Ekici, Arif, Vieth, Michael, Backert, Steffen, Linz, Bodo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120309/
https://www.ncbi.nlm.nih.gov/pubmed/37193047
http://dx.doi.org/10.1016/j.cellin.2022.100032
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author Sharafutdinov, Irshad
Ekici, Arif
Vieth, Michael
Backert, Steffen
Linz, Bodo
author_facet Sharafutdinov, Irshad
Ekici, Arif
Vieth, Michael
Backert, Steffen
Linz, Bodo
author_sort Sharafutdinov, Irshad
collection PubMed
description Infection of the stomach by Helicobacter pylori is a major risk factor for the development of gastric cancer. Colonization of the gastric epithelium leads to the activation of multiple disease-related signaling pathways. Serine protease HtrA represents an important secreted virulence factor that mediates cleavage of cellular junctions. However, its potential role in nuclear responses is unknown. Here, we performed a genome-wide RNA-seq analysis of polarized gastric epithelial cells infected by wild-type (wt) and ΔhtrA mutant bacteria. Fluorescence microscopy showed that H. pylori wt, but not ΔhtrA bacteria, preferably localized at cellular junctions. Our results pinpointed early (2 h) and late (6 h) transcriptional responses, with most differentially expressed genes at 6 h post infection. The transcriptomes revealed HtrA-dependent targeting of genes associated with inflammation and apoptosis (e.g. IL8, ZFP36, TNF). Accordingly, infection with the ΔhtrA mutant induced increased apoptosis rates in host cells, which was associated with reduced H. pylori CagA expression. In contrast, transcription of various carcinogenesis-associated genes (e.g. DKK1, DOCK8) was affected by H. pylori independent of HtrA. These findings suggest that H. pylori disturbs previously unknown molecular pathways in an HtrA-dependent and HtrA-independent manner, and provide valuable new insights of this significant pathogen in humans and thus potential targets for better controlling the risk of malignant transformation.
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spelling pubmed-101203092023-05-15 Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori Sharafutdinov, Irshad Ekici, Arif Vieth, Michael Backert, Steffen Linz, Bodo Cell Insight Research article Infection of the stomach by Helicobacter pylori is a major risk factor for the development of gastric cancer. Colonization of the gastric epithelium leads to the activation of multiple disease-related signaling pathways. Serine protease HtrA represents an important secreted virulence factor that mediates cleavage of cellular junctions. However, its potential role in nuclear responses is unknown. Here, we performed a genome-wide RNA-seq analysis of polarized gastric epithelial cells infected by wild-type (wt) and ΔhtrA mutant bacteria. Fluorescence microscopy showed that H. pylori wt, but not ΔhtrA bacteria, preferably localized at cellular junctions. Our results pinpointed early (2 h) and late (6 h) transcriptional responses, with most differentially expressed genes at 6 h post infection. The transcriptomes revealed HtrA-dependent targeting of genes associated with inflammation and apoptosis (e.g. IL8, ZFP36, TNF). Accordingly, infection with the ΔhtrA mutant induced increased apoptosis rates in host cells, which was associated with reduced H. pylori CagA expression. In contrast, transcription of various carcinogenesis-associated genes (e.g. DKK1, DOCK8) was affected by H. pylori independent of HtrA. These findings suggest that H. pylori disturbs previously unknown molecular pathways in an HtrA-dependent and HtrA-independent manner, and provide valuable new insights of this significant pathogen in humans and thus potential targets for better controlling the risk of malignant transformation. Elsevier 2022-05-25 /pmc/articles/PMC10120309/ /pubmed/37193047 http://dx.doi.org/10.1016/j.cellin.2022.100032 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research article
Sharafutdinov, Irshad
Ekici, Arif
Vieth, Michael
Backert, Steffen
Linz, Bodo
Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori
title Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori
title_full Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori
title_fullStr Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori
title_full_unstemmed Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori
title_short Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori
title_sort early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen helicobacterpylori
topic Research article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120309/
https://www.ncbi.nlm.nih.gov/pubmed/37193047
http://dx.doi.org/10.1016/j.cellin.2022.100032
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